Project Summary/Abstract Vision loss is a devastating medical problem that generates significant medical costs, directly as well as indirectly in the form of decreased productivity, lower quality of life, and loss of independence among those affected. In the United States, disorders of the eye result in a significant economic burden for society. Because the human retina has minimal or no regenerative ability, loss of retinal neurons due to intrinsic defects or environmental insults is generally irreversible, making this the most common cause of permanent visual impairment. In this project, the candidate proposes to study the development of retinal ganglion cells, the output projection neurons that connect the eye with the brain. These neurons are vulnerable to injury in traumatic optic nerve injuries and to diseases such as glaucoma, and a deeper understanding of their development and regeneration could have significant implications for reversing visual impairment. In the first part of this application, the candidate proposes to investigate the function of a transcription factor expressed by retinal ganglion cells in a mouse line with this gene conditionally deleted, and by using overexpression in retinal progenitor cells in vivo. In the second part of this application, the candidate proposes to screen a candidate list of transcription factors by overexpression in vivo for their ability to reprogram endogenous retinal cells to produce new retinal ganglion cells. Overall, insights from the study of normal retinal ganglion cell development will be applied to develop methods for replacing these cells when they are damaged or diseased. The candidate?s overall career goal is to understand developmental processes that shape the nervous system, and to apply this developmental knowledge to regenerate neurons lost to injury or disease. The candidate has a deep background in cerebral cortical developmental biology and proposes to receive training in retinal development because the retina is significantly more accessible to clinical manipulation, and promising regenerative therapies are already beginning to come to fruition. During the mentored phase of this award, the candidate will prioritize undertaking activities to increase understanding of retinal development, to do productive and meaningful science, and consequently to transition research from cerebral cortical development to retinal development. The PI will work with mentors Dr. Jeffrey Goldberg and Dr. Sui Wang, together with members of a Stanford faculty advisory team. The proposed research and training plans will take place in the laboratory of Dr. Jeffrey Goldberg, chair of the Department of Ophthalmology at Stanford University School of Medicine. The outstanding vision science group at Stanford is embedded within the world-class neuroscience and broader life sciences community at Stanford as a whole, with benefits of a close-knit and focused department and the resources of the wider university.